Endotoxin Stimulates Hepatocyte Interleukin-6 Production

Panesar, Ninder; Tolman, Kim; Mazuski, John E.

doi:10.1006/jsre.1999.5648

Cited by 52 publications

(42 citation statements)

References 45 publications

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“…It is well established that IL-6, produced by Kupffer cells and hepatocytes, 35 is the central trigger of LR via phosphorylation/ activation of STAT3. 36 However, excessive levels of IL-6 following PH halt hepatocyte proliferation 17 by increasing p21 transcription to block Cyclin/CDK complexes 37 and by binding STAT3 to inhibit its pro-regenerative signals.…”

Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

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Section: Discussionmentioning

confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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“…4 TLR4 is expressed in hepatocytes and endotoxin can induce the secretion of TNFand interleukin-6, ect by hepatocytes. [6][7][8][9][10][11] TLR4 is up-regulated in peripheral blood monocytes (PBMCs) and hepatocytes in patients with chronic hepatitis C(CHC) and plays an important role in the pathogenesis of CHC. 12,13 Systemic endotoxemia often occurs in patients with chronic viral hepatitis 14 and the human 60 kDa heat shock proteins (hHSP 60) are markedly increased in patients with active viral hepatitis with predominant expression in areas of inflammatory infiltrates 15 , while endotoxin and hHSP 60 are the major ligands of TLR4, an important member of TLRs.…”

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confidence: 99%

The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B

Wei¹,

Guo²,

Liu³

et al. 2008

CIM

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Results: TLR4 expressed mainly in the cytoplasm and some on cell membrane in hepatocytes. The staining scores of TLR4 expression in the liver tissues of patients with CHB were significantly higher than that of healthy controls. The liver tissues from patients with severe CHB expressed higher level of TLR4 than those from patients with mild CHB. Furthermore, the staining scores of TLR4 expression in the liver tissues of patients with CHB were positively correlated with the grading scores. Our results also showed that the mean fluorescence intensity and TNFsecretion induced by endotoxin as well as the protein and mRNA 1eve1s of TLR4 in HepG2.2.15 cells were all significantly higher than those in HepG2 cells. Conclusion: TLR4 was up-regulated in the hepatocytes in patients with CHB. This indicates a potentially important interaction between TLR4 expression and the pathogenesis of CHB.Mechanisms responsible for chronic hepatitis B remain incompletely understood, although increasing evidence points to immunological rather than direct viral effects playing a central role. 1,2 However, most studies have focused on adaptive immunity, with little research on the innate immunity. One of the key components of the innate immune response is the family of Toll-like receptors(TLRs), evolutionarily conserved pattern recognition receptors. Activation of TLRs triggered by various motifs common to microorganisms, known as pathogen-associated molecular patterns, can promote the inflammatory response, the antiinfectious response and the maturation of antigen pre-ORIGINAL RESEARCH

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“…activity was due to endogenously released inflammatory cytokines, such as IL-6, interferon, tumor necrosis factor-␣, and IL-1 (RuffJamison et al, 1994;Morgan, 1997;Panesar et al, 1999;Siewert et al, 2000). The suppression of P450-mediated metabolism of endogenous and exogenous substances under inflammatory conditions is an important consideration for drug efficacy and drug-drug interactions (Sheldlofsky et al, 1994;Liu et al, 2000).…”

mentioning

confidence: 99%

Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

Pan

Xiang²,

Ball³

et al. 2003

Drug Metab Dispos

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ABSTRACT:Signal transducer and activator of transcription (Stat), a family of transcriptional factors, has been demonstrated to play a critical role in gene regulation in response to inflammatory cytokines, such as interferon and interleukin-6. Inflammatory cytokines and bacterial endotoxin are known to suppress, in most of cases, the constitutive or induced cytochromes P450 (P450) in animals and humans. However, it is not clear if the suppression of P450 by cytokines is through the Stat-signaling pathway. In the present study, we determined whether Stat1 is involved in lipopolysaccharide (

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Endotoxin Stimulates Hepatocyte Interleukin-6 Production

Cited by 52 publications

References 45 publications

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

The significance of Toll-like receptor 4 (TLR4) expression in patients with chronic hepatitis B

Lipopolysaccharide-Mediated Modulation of Cytochromes P450 in Stat1 Null Mice

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